New Onset Diabetes and Nephropathy after Renal Transplantation

Newo nset diabetes mellitus after transplantation (NODAT) is an important complication after kidney transplantation, responsible for increased mortality mainly related to cardiovascular events and infections. It has been also identified as an independent risk factor associated with graft loss. The varying definitions of diabetes used in the literature, and the prevalence and incidence of NODAT, are difficult to establish: it varies from 2 to 50% in the kidney transplant population. However, using the World Health Organization and the American Diabetes Association criteria, it occurs in ~15% of transplant recipients at 1 year in the USA, and ~5–1 0% in Europe. The main recipientr elated risk factors include old age, high body weight and high body mass index (BMI) before transplantation, Afro American or Hispanic ethnicity, hepatitis C virus (HCV) infection, and impaired fasting glucose level before transplantation. The other significant risk factors include male donor, acute rejection episodes, cytomegalovirus (CMV) infection and the immunosuppressive regimen, especially the use of tacrolimus (FK506), steroids, or mammalian target for rapamycin inhibitors. While some risk factors cannot be modified, others, such as recipient body weight, BMI, HCV or CMV infection, and immunosuppressive regimen can be controlled with an appropriate diet or treatment. Screening for impaired fasting glucose should be done before transplantation in dialysis or end stage renal disease patients to identify patients at risk for NODAT. In patients with increased BMI, weight loss before transplantation reduces the risk of NODAT. HCV infection should be treated before transplantation. Prolonged antiC MV prophylaxis may be used. Cyclosporine A is preferred to tacrolimus in patients at high risk of NODAT. A steroidf ree regimen or early steroid withdrawal is encouraged to reduce the risk of NODAT.

Prevention of Diabetic Nephropathy

Lai KN, Tang SCW (eds): Diabetes and the Kidney.

Contrib Nephrol Basel, Karger, 2011, vol 170, pp 247–255

New- Onset Diabetes and Nephropathy

after Renal Transplantation

a Department of Nephrology, Dialysis, and Organ Transplantation, CHU Rangueil, and

b INSERM U563, IFR- BMT, CHU Purpan, Toulouse, France

Abstract

New- onset diabetes mellitus after transplantation (NODAT) is an important complication

after kidney transplantation, responsible for increased mortality mainly related to

car-diovascular events and infections It has been also identified as an independent risk

fac-tor associated with graft loss The varying definitions of diabetes used in the literature,

and the prevalence and incidence of NODAT, are difficult to establish: it varies from 2 to

50% in the kidney transplant population However, using the World Health Organization

and the American Diabetes Association criteria, it occurs in ~15% of transplant recipients

at 1 year in the USA, and ~5– 10% in Europe The main recipient- related risk factors

include old age, high body weight and high body mass index (BMI) before

transplanta-tion, Afro- American or Hispanic ethnicity, hepatitis C virus (HCV) infectransplanta-tion, and impaired

fasting glucose level before transplantation The other significant risk factors include

male donor, acute rejection episodes, cytomegalovirus (CMV) infection and the

immu-nosuppressive regimen, especially the use of tacrolimus (FK506), steroids, or mammalian

target for rapamycin inhibitors While some risk factors cannot be modified, others, such

as recipient body weight, BMI, HCV or CMV infection, and immunosuppressive regimen

can be controlled with an appropriate diet or treatment Screening for impaired fasting

glucose should be done before transplantation in dialysis or end- stage renal disease

patients to identify patients at risk for NODAT In patients with increased BMI, weight loss

before transplantation reduces the risk of NODAT HCV infection should be treated before

transplantation Prolonged anti- CMV prophylaxis may be used Cyclosporine A is

pre-ferred to tacrolimus in patients at high risk of NODAT A steroid- free regimen or early

steroid withdrawal is encouraged to reduce the risk of NODAT.

Copyright © 2011 S Karger AG, Basel

The introduction of novel immunosuppressive drugs has allowed a significant

decrease in the incidence of allograft rejection after renal transplantation

Patient and graft survival rates, however, have not significantly improved [1],

partly because of the increased burden of posttransplant complications,

includ-ing new- onset diabetes mellitus after transplantation (NODAT)

Harmful Effect of New- Onset Diabetes Mellitus after Renal Transplantation

Increased mortality has been reported in patients with NODAT compared to

patients without NODAT [2], mainly due to cardiovascular complications, but

also because of an increased incidence of infections Compared to kidney

trans-plant patients without NODAT, diabetic patients have a higher incidence and

greater severity of infections, which results in increased posttransplant

mortal-ity [2]

Cosio et al [3] have shown that the 5- year cumulative incidence of

cardio-vascular events was correlated with fasting glucose level at 1 year after

trans-plantation [3] The incidence of cardiovascular events was significantly higher

in patients with diabetes or a moderately elevated fasting glucose level

com-pared to those with a normal fasting glucose level at 1 year after

transplanta-tion In addition, a multivariate analysis identified fasting glucose levels at 1,

4, and 12 months after transplantation, as independent predictive factors for

a cardiovascular event occurring after kidney transplantation [3] In a

pro-spective study, Ducloux et al [4] had shown that NODAT is an independent

risk factor for the appearance of atheromatous disease in kidney transplant

patients (RR = 1.34, 95% CI 1.04– 2.18) Pretransplantation diabetes is also a

predictive factor for all- cause and cardiovascular mortality after kidney

trans-plantation [5]

NODAT also accounts for lower graft survival [2] and is an independent risk

factor associated with graft loss [6] At 5 years, graft function, as defined by

serum creatinine level, is significantly lower in NODAT patients compared to

patients without NODAT [6] Authentic biopsy- proven diabetic nephropathy

has been reported in patients who develop NODAT

Moreover, classic complications of diabetes mellitus, such as ketoacidosis,

hyperosmotic diabetic coma, or peripheral neuropathy, have been described in

renal- allograft patients with NODAT [6] NODAT also has an impact on the

quality of life of transplant patients and represents an important economic

bur-den [7]

Prevalence and Incidence of New- Onset Diabetes Mellitus after Renal

Transplantation

The varying definitions of diabetes used in the literature and the prevalence and

incidence of NODAT are difficult to establish

According to the World Health Organization (WHO) and the American

Diabetes Association (ADA), diabetes is currently defined by the association of

diabetes symptoms (polyuria, polydipsia, weight loss) and a fasting glucose level

≥7 mm (1.26 g/dl), or a nonfasting glucose level of ≥11.1 mm (2 g/dl), or the use

of insulin and/or oral antidiabetic drugs Impaired glucose tolerance is defined

by a fasting glucose level between 6.1 and 7 mm Abnormal glucose levels must

be assessed twice to confirm diagnosis

The prevalence and incidence of diabetes is higher in transplant patients

than in the general population, and is estimated to be between 2 and 50%

according to the literature [8] NODAT usually occurs in the first 3

post-transplantation months [8] Using the USRDS registry, Kasiske et al [2]

esti-mated the cumulative incidence of NODAT in patients who had received a

first renal allograft between 1996 and 2000 Patients were considered diabetic

if reported to the Medicare system The cumulative incidences were 9.1, 16,

and 24% at 3, 12, and 36 months, respectively [2] Using the WHO/ADA

cri-teria for diabetes, Cosio et al [3] reported a prevalence of impaired glucose

tolerance and NODAT in 33 and 13% of patients, respectively, at 1 year after

transplantation [3]

A French multicenter observational study that included 527 patients

identi-fied using WHO criteria reported a NODAT prevalence of 7%, with a median

time until NODAT onset of 1.6 months [9] Impaired fasting glucose was found

in 7.9% of patients [9] Diabetes is probably underestimated in the majority of

studies For example, in 122 renal transplant patients in whom fasting glucose

levels were between 5.6 and 6.1 mm, and who had undergone an oral glucose

tolerance test (OGT), the occurrence of NODAT, impaired fasting glucose,

or high fasting glucose levels were diagnosed in 10, 14, and 18% of patients,

respectively [10]

Similarly, with the help of an OGT, Porrini et al [11] reported a 33%

inci-dence of impaired fasting glucose and a 20% inciinci-dence of NODAT in 154

nondiabetic renal transplant patients receiving a tacrolimus- based

immunosup-pressive regimen in the first year after kidney transplantation [11] Conversely,

a normal fasting glucose level and a normal OGT at day 5 after transplantation

are independent protective factors against NODAT [12]

Risk Factors for New- Onset Diabetes Mellitus after Transplantation

Numerous studies have identified risk factors associated with NODAT (table 1)

[13] The main recipient- related risk factors include old age, high body weight

and high body mass index (BMI) before transplantation, Afro- American or

Hispanic ethnicity, hepatitis C virus (HCV) infection, and an impaired fasting

glucose level before transplantation Weight gain during the first

posttransplan-tation year does not seem to be associated with NODAT The polymorphism

of the promoter region of interleukin- 6, in the position 174(G→C), has been

associated not only with type 2 diabetes and insulin resistance, but also with

NODAT [14] The rs7903146 polymorphism of transcription factor- 7- like 2 was

also significantly associated with NODAT in a population of 1,229 kidney

trans-plant patients (OR 1.55, p = 0.02, for the CT genotype, and OR 1.79, p = 0.04, for

the TT genotype) [15]

The other significant risk factors associated with transplantation are

gen-der (male donors), acute rejection episodes, cytomegalovirus (CMV)

infec-tion, and the immunosuppressive regimen, especially the use of tacrolimus

(FK506), steroids, and mammalian target for rapamycin inhibitors An

induc-tion therapy with basiliximab has been recently identified as a risk factor for

NODAT [16] Basiliximab, a monoclonal antibody directed against the

recep-tor of interleukin- 2 (CD25), inhibits CD4+ CD25+ lymphocytes that include

Table 1. Main risk factors for new-onset diabetes mellitus after kidney transplantation

Recipients’ factors – older age

– male gender (controversial) – family history of diabetes – weight at transplantation – high BMI before transplantation – maximum BMI before transplantation – Afro-American or Hispanic ethnicity – low educational status

– HCV infection – fasting glucose level before transplantation – impaired fasting glucose level before transplantation – metabolic syndrome:

high triglyceride level low high-density lipoprotein level Transplantation factors – male donor

– cadaveric donor (controversial) – number of HLA mismatches (controversial) – occurrence of at least one episode of acute rejection – CMV infection

– immunosuppressive regimen:

use of tacrolimus tacrolimus trough levels steroid pulses

high steroid daily dosage high cumulative dose of steroids use of mTOR inhibitors

HLA = Human leukocyte antigen; mTOR = mammalian target for rapamycin.

regulatory CD25+ CD4+ FOXP3+ T cells Apparently, these

subpopula-tions play a role in the development of diabetes, in particular type 1 diabetes

[16] Although there is no clear pathophysiological explanation, it has been

shown that albuminuria on day 5 after transplantation [12], and

albuminu-ria at months 3 and 6 after transplantation [17], are associated with NODAT

Adiponectin, an anti- inflammatory protein synthesized by adipocytes, reduces

insulin resistance and atheromatosis Elevated adiponectin levels appear to

prevent NODAT [18]

Although some risk factors cannot be modified, others, such as

recipi-ent body weight and BMI, HCV or CMV infection, and the

immunosup-pressive regimen, could be controlled with an appropriate diet or modified

treatment

Measures to Reduce New- Onset Diabetes Mellitus after Transplantation

Risk Factors?

Screening for Impaired Fasting Glucose before Transplantation

Screening for impaired fasting glucose should be done before transplantation

in dialysis or end- stage renal disease patients to identify patients at risk for

NODAT, in order to ensure meticulous posttransplantation surveillance of

gly-cemic levels and to adapt the immunosuppressive regimen

Reducing Excess Weight before Transplantation

In patients with increased BMI, weight loss before transplantation reduces the

risk of NODAT, cardiovascular events, and postoperative complications

Treatment of HCV Infection before Transplantation

A meta- analysis has shown that the relative risk of NODAT is 3.97- fold greater

(CI 95%: 1.83– 8.61) in HCV- positive renal transplant patients compared to

HCV- negative renal transplant patients [19] In HCV- positive patients, NODAT

may occur more frequently in patients treated with tacrolimus compared to

those receiving cyclosporine A (CsA; 57.8 vs 7.7%, p < 0.0001) [20] However,

the mechanism by which HCV favors NODAT is not well established HCV may

affect glucose metabolism by inducing hepatocyte necrosis Moreover, a link

between HCV infection and insulin resistance has been established in vitro and

in vivo Finally, HCV could induce dysregulation in the hepatocyte production

of cytokines and insulin receptors

As treatment of HCV infection is contraindicated after kidney

transplanta-tion because of the high risk of interferon therapy- induced acute rejectransplanta-tion, it is

recommended to treat all prospective HCV- positive, RNA- positive, renal

trans-plantation candidates in order to achieve viral eradication before

transplanta-tion [21]

Reducing the Risk of Cytomegalovirus Infection

The risk of CMV primary infection or reactivation can be reduced by extended

prophylaxis of CMV infection in patients at risk for NODAT

Selection of Immunosuppressive Regimen

Calcineurin Inhibitors

Tacrolimus seems more prone to induce NODAT than CsA In a meta- analysis

that evaluated the effect of different calcineurin inhibitors (CNIs) on the

inci-dence of NODAT, Heisel et al [22] found a higher inciinci-dence of NODAT in

patients receiving FK506 than patients receiving CsA (9.8 vs 2.7%, RR = 3.7,

CI 95%: 2.6– 15.36, p < 0.0001) The DIRECT Study is an international

multi-center randomized study that compared the incidence of NODAT in de novo

renal transplant recipients who received either CsA or FK506 [23] Amongst

the nondiabetic patients before transplantation, the incidence of NODAT at

6 months after transplantation was 26% in the CsA arm and 33.6% in the

FK506 arm (p = 0.0046) At 6 months, 8.9% of patients receiving CsA and

16.8% of patients receiving FK506 had received treatment for diabetes (p =

0.005) [23]

The economic impact of immunosuppressive regimen- induced diabetes was

evaluated to be USD 2,025 and USD 3,308 per patient receiving tacrolimus at 1

and 2 years after transplantation, respectively, while similar figures for patients

receiving CsA were only USD 1,137 and USD 1,611, respectively [7]

Both CsA and FK506 induce diabetes by reducing insulin secretion and

also, to a lesser extent, by inducing insulin resistance [24] Insulin resistance

is increased by concomitant administration of steroids [24] Asberg et al [25]

have shown that, at 1 year after transplantation, insulin sensitivity was

signifi-cantly improved in patients who had never received CNIs compared to patients

treated with CNIs The different tissue localizations of the molecular targets of

CsA and FK506 could account for the greater impact of FK506 on NODAT

Indeed, FKBP12, the target of FK506, is highly expressed in β- cells in the islets

of Langerhans, whereas CsAs, which target cyclophilin, is mostly expressed in

the heart, liver, and kidney

Conversion from tacrolimus to cyclosporine in patients with NODAT

significantly improves fasting glucose levels and glycated hemoglobin compared

to patients maintained on tacrolimus [26] At 1- year after conversion, remission

of NODAT, as defined by fasting glucose levels <1.26 g/l without any antidiabetic

treatment, was observed in 42% of converted patients versus 0% of patients

maintained on tacrolimus (p = 0.001) [26] The concomitant interruption of

steroids also increases the advantage of conversion Conversely, Luan et al [27]

recently showed that a switch from CsA to FK506 at 11.4 months (range: 0.3–

83.8) after transplantation in 171 patients did not increase the incidence of

NODAT or impaired glucose tolerance when compared to 533 patients

main-tained on CsA, during a mean follow- up time of 31.5 ± 21.6 months

1 Pascual J, Galeano C, Royuela A, Zamora J:

A systematic review on steroid withdrawal

between 3 and 6 months after kidney

trans-plantation Transplantation 2010;90:343– 349.

2 Kasiske BL, Snyder JJ, Gilbertson D, Matas

AJ: Diabetes mellitus after kidney

transplan-tation in the United States Am J Transplant

2003;3:178– 185.

3 Cosio FG, Kudva Y, van der Velde M, Larson

TS, Textor SC, Griffin MD, Stegall MD: New

onset hyperglycemia and diabetes are

associ-ated with increased cardiovascular risk after

kidney transplantation Kidney Int 2005;

67:2415– 2421.

4 Ducloux D, Kazory A, Chalopin JM:

Posttransplant diabetes mellitus and athero-sclerotic events in renal transplant recipients:

a prospective study Transplantation 2005;79:

438– 443.

5 Kuo HT, Sampaio MS, Vincenti F, Bunnapradist S: Associations of pretrans-plant diabetes mellitus, new- onset diabe-tes after transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database Am J Kidney Dis 2010;56:1127– 1139.

Steroid Avoidance or Steroid Reduction

Cumulative dose and daily steroid dosages are associated with an increased

incidence of NODAT [13], essentially through enhanced insulin resistance

Immunosuppressive regimens based on steroid minimization have shown a

lower incidence of NODAT At 6 months after transplantation, the incidence of

NODAT was 0.4% in patients receiving a steroid- free immunosuppressive

regi-men compared to 5.4% in patients receiving steroids [28] Steroid withdrawal

within the first week after transplantation significantly reduced the incidence

of NODAT at 1 year compared to patients who were continued on steroids [29]

or compared to patients in whom steroids were withdrawn between 3 and 6

months after transplantation [1] Conversely, comparison study of early steroid

withdrawal by day 7 versus continuation of low- dose steroids in de novo renal

transplant patients did not reveal any significant difference in the incidence of

NODAT at 5 years after transplantation [30] However, the number of patients

developing NODAT that required insulin therapy was significantly lower in

the group of patients with early steroid withdrawal compared to the ‘low dose’

group [30] Finally, a recent meta- analysis has shown that steroid withdrawal

between 3 and 6 months after transplantation does not reduce the incidence

of NODAT [1] Thus, only a steroid- free regimen or early steroid withdrawal

reduces the incidence of diabetes

Conclusion

The incidence of de novo diabetes after renal transplantation is higher than that

in the general population, and accounts for a decrease in patient and graft

sur-vival rate Among the identified risk factors, some can be controlled in order to

reduce the incidence of NODAT

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Nassim Kamar, MD, PhD

Department of Nephrology, Dialysis, and Organ Transplantation

CHU Rangueil, TSA 50032

FR– 31059 Toulouse Cedex 9 (France)

Tel +33 5 61 32 23 35, Fax +33 5 61 32 39 89, E- Mail kamar.n@chu- toulouse.fr